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Requirement for Etoposide in the Treatment of Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis

From the Kyoto City Institute of Health and Environmental Sciences; Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto; Division of Pediatrics, Hamanomachi Hospital, Fukuoka; Division of Hematology, Chiba Children’s Hospital, Chiba; Department of Pediatrics, Gunma University School of Medicine, Gunma; and Division of Pediatrics, Osaka City General Hospital, Osaka, Japan.

Address reprint requests to Shinsaku Imashuku, MD, Kyoto City Institute of Health and Environmental Sciences, 1-2, Higashitakada-cho, Mibu, Nakagyo-ku, Kyoto, Japan 604-8845; email: shinim95@ mbox.kyoto-inet.or.jp.

PURPOSE: We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH).

PATIENTS AND METHODS: Among the factors tested were age at diagnosis (< 2 years or 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide.

RESULTS: By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% ± 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% ± 6.9% v 56.5% ± 12.6% for patients receiving this agent later or not at all; P < .01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P = .04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment.

CONCLUSION: We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.

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